GB1037659A - Thiepin derivatives and process for the preparation - Google Patents

Abstract

The invention comprises compounds of the formula <FORM:1037659/C2/1> wherein X1 and X2 independently of each other represent hydrogen, chlorine or bromine atoms, Y1 alone represents hydrogen or a C1- 2 alkyl radical, Y2 alone represents hydrogen or Y1 and Y2 together represent an additional bond, R1 represents a hydrogen atom or a C1- 2 alkyl radical, R2 represents a C1- 4 alkyl radical, R3 represents a hydrogen atom or a C1- 4 alkyl radical and n represents 0 or 1, and their salts with inorganic and organic acids. The compounds are prepared by reducing a compound of the formula <FORM:1037659/C2/2> by means of a complex hydride in an organic solvent, and, if desired, converting a resulting compound into a salt with an organic or inorganic acid. Acid amides of Formula II are prepared by reacting the corresponding acid chlorides (obtained by reaction of the free acid with thionyl chloride) or corresponding p-nitrophenyl or methyl esters with the appropriate amine. They may also be prepared by reacting the corresponding acids with sulphurous acid alkyl ester dialkylamides (having not more than 4 carbon atoms in each alkyl group), or with alkyl isocyanates, having not more than four carbon atoms in the alkyl group, followed by heating until CO2 is split off, or by reacting salts of the corresponding acids with dialkyl carbamic acid chlorides, having not more than 4 carbon atoms in each alkyl group, followed by heating. Dibenzo [b,f] thiepin - 10 - acetic acids of the formula <FORM:1037659/C2/3> are prepared by reacting an appropriate dibenzo [b, f] thiepin - 10(11H) - one with a methylating agent to produce the corresponding 10-oxo-11-methyl compound, reducing this compound to the 10-hydroxy-11-methyl compound, converting the hydroxy compound to the 10-chloro-11-methyl compound, splitting off hydrogen chloride to form the 10-methyl-dibenzo [b,f]-thiepin, treating this compound with N-bromo succinimide to form the 10-bromomethyl compound, reacting this compound with an alkali metal cyanide to form the 10-cyanomethyl compound and then hydrolysing this compound to the dibenzo [b, f] thiepin-10-acetic acid. The 10-methyl-dibenzo [b, f] thiepins of the above reaction scheme may also be prepared by reacting an appropriate dibenzo [b, f] thiepin-10(11H)-one with a methyl magnesium halide and splitting off water in the 10-methyl-10-hydroxy compound obtained. Dibenzo [b,f] thiepin - 10 - propionic acids of the formula: <FORM:1037659/C2/4> where Y1 and Y2 together represent an additiona bond are prepared by reacting an appropriate 10 - bromomethyl - dibenzo [b,f] thiepin with a cyanoacetic acid alkyl ester, malonic acid dialkyl ester or an a -alkyl derivative thereof, hydrolysing the resulting a -(dibenzo [b,f] thiepin- 10 - yl - methyl) - cyanoacetic acid alkyl ester, or -malonic acid dialkyl ester to form the corresponding diacid and partially decarboxylating the diacid. The acids of Formula III, wherein Y1 represents a C1- 2 alkyl radical and Y2 represents hydrogen, are prepared by alkylating an appropriate dibenzo [b, f] thiepin-10(11H)-one in the 11-position, reacting the resulting 10 - oxo - 11 - alkyl compound with acrylonitrile, acrylic acid alkyl ester or an a -alkyl derivative thereof to produce the oxocarboxylic acid nitrile or oxocarboxylic acid alkyl ester, hydrolysing these to the oxocarboxylic acid and thereafter removing the oxo group. Pharmaceutical compositions having histamine antagonistic and adrenolytic activity, for oral or parenteral administration, comprise a compound of the invention together with a pharmaceutical carrier, e.g. water,